PROJECT SUMMARY Peptide therapeutics combine high potency and selectivity with fewer side effects than traditional small molecules. This has fueled interest in peptides filling the gap between ?biologics? and small molecules as compounds that have the key desired properties from both the other classes. Worldwide peptide drug sales surpassed $20 billion in 2015, of which nearly $10 billion was in the USA, with projected growth of 10% per year. Synthesis and purification of long peptides continue to be major challenges for manufacturers. Solid-phase peptide synthesis (SPPS) is the most versatile approach to the synthesis of peptides containing fewer than 50 amino-acid residues. SPPS enables the incorporation of unnatural elements with desired functionality (e.g., increases in conformational and proteolytic stability and potency/efficacy at target receptors). While current SPPS methods routinely yield high efficiencies per coupling step, for a 40-mer peptide a 97% individual step coupling efficiency would yield only ~30% of full-length peptide and ~70% of peptides lacking at least one amino-acid residue (deletions). Purification generally involves chromatographic separation, which is generally viewed as the ?bottleneck? for peptide synthesis. Moreover, deletions that differ from the full sequence by only a single residue are frequently very challenging to separate using chromatography. The Kumar group has developed an original F-capping SPPS methodology to simplify and accelerate the process of purification. Briefly, at difficult steps of peptide assembly, truncation sequences are terminated by inert fluorocarbon segments (F-caps), and thus are prevented from growing into intractable contaminants. We will synthesize long and challenging peptide sequences rapidly and in high purity. We aim to reduce the time to synthesize a typical 30-amino acid long sequence in the laboratory from a week to four hours or less, at the same time eliminating deletions. To this end we will combine the high-temperature Fast Flow technology with our F-Capping technology. Fast Flow is known for shortened cycle times of minutes vs. hours, but it does not address deletions. F-Capping suppresses deletions via minute-long treatments with a ?fluorous? reagent. The tandem use of these technologies is expected to afford candidate peptide drugs at a fraction of the time and cost.